A multitude of genes are known to affect lipoprotein metabolism and the propensity for coronary heart disease (CHD). This project involves the use of mouse models of atherosclerosis for studying the in vivo effect of a variety of genes related to lipid metabolism and their potential impact on atherosclerosis.[unreadable] ABCA1: ABCA1 is a key transporter that is involved in the efflux of excess cellular cholesterol to lipid-poor HDL. It is also the defective gene in Tangier disease, an autosomal recessive disorder associated with low HDL and increased incidence for CHD. In order to better understand its tissue specific effect on lipid metabolism and atherosclerosis, transgenic mice over expressing ABCA1 in endothelial cells were produced, using the Tie2 promoter. Approximately a 30-fold increase in ABCA1 mRNA was observed in endothelial cells isolated from transgenic mice. These cells were also observed to have a 2-fold increase in cholesterol efflux to apoA-I compared to control endothelial cells. No changes were observed in serum lipoproteins, but when placed on a high fat diet the mice were protected against atherosclerosis, indicating the importance of endothelial expression of ABCA1 in the pathogenesis of atherosclerosis[unreadable] ABCG1: ABCG1 is a key transporter that is involved in the efflux of excess cellular cholesterol to lipid-rich HDL, and hence it would be predicted to have an anti-atherogenic effect. ABCG5/G8 are half-transporters form a heterodimeric complex and are involved in cholesterol and phytosterol secretion into the bile and the lumen of the gut. They are the defective genes in Sitosterolemia, which is a disorder associated with increased atherosclerosis due to the hyperabsorption of plant sterols and other sterols. ABCG1 transgenic mice were crossed with ABCG5/G8 transgenic mice and were examined for biliary lipid excretion. ABCG1 was found to potentiate the ability of ABCG5/G8 to secrete cholesterol into the bile but had no effect on biliary secretion of phospholipids or bile salts. Over expression of just ABCG1, however, had no effect on biliary cholesterol excretion. These results suggest that under conditions of maximal biliary excretion by ABCG5/G8, hepatic pools of cholesterol destined for secretion into the bile may be limited and that ABCG1 works cooperatively with ABCG5/G8 in mobilizing cholesterol for biliary sterol excretion.